Nausea and vomiting are common and feared symptoms among cancer patients; up to 80% of patients experience chemotherapy-induced nausea and vomiting (CINV) without prophylactic therapy. The syndrome may have a significant impact on the treatment and quality of life as patients may delay or even cancel scheduled chemotherapies. Generally, CINV syndrome can be categorized as acute, delayed or anticipatory. In acute CINV, nausea and vomiting appear within the first 24 hours after chemotherapy, while in the case of delayed CINV, symptoms can last for several days. Anticipatory CINV is a conditional response that occurs in patients who had poorly controlled CINV symptoms during a previous course of chemotherapy.
Until recently the prevention and treatment of CINV symptoms involved the use of corticosteroids, dopamine D2 antagonists and serotonin 5-HT3 receptor antagonists. Therapies consisting of serotonin 5-HT3 receptors (such as Kytril® (granisetron), Zofran® (ondansetron), Anzemet® (dolesetron), Aloxi® (palonosetron) and Navoban® (Tropisetron)). Aloxi® (palonosetron), due to its longer half-life, is the only serotonin 5-HT3 receptor antagonist currently approved for the prevention of both acute and delayed CINV. Usually, a combination of Aloxi® and a corticosteroid, administrated prior to chemotherapy, followed by administration of one or both agents for several days is used for the prevention of delayed CINV. However, unpleasant adverse-effects due to the multiple dosing of 5-HT3 receptor antagonist during the treatment of delayed CINV symptoms, such as headache and constipation, led to the addition of neurokinin 1 (NK1) receptor antagonists, such as Aprepitant or Fosaprepitant, in the treatment regimen.
Aprepitant is a highly-selective antagonist of NK1 receptors with little or no affinity for serotonin, dopamine or corticosteroid receptors. It is available in the form of capsules for oral administration (Emend®) containing either 40 mg, 80 mg, or 125 mg of aprepitant. Unfortunately, oral capsule formulations are easy to swallow for patients undergoing chemotherapy or postoperative condition since such capsules themselves often induce nausea and vomiting.
Fosaprepitant is a water-soluble phosphorylated prodrug of aprepitant, which may be administered intravenously. Fosaprepitant has been reported to undergo rapid conversion to aprepitant in less than 30 minutes after an IV infusion.
Fosaprepitant Dimeglumine for Injection (Emend® for Injection) is sold as a lyophilized prodrug of aprepitant. To administer, a small about of saline is combined with the lyophilized powder, and then transferred to an infusion bag to yield a final concentration of 1 mg/ml. Care must be taken during the initial dilution to prevent foaming. The reconstituted final drug solution is reported to be stable only for 24 hours at ambient room temperature (at or below 25° C.) after reconstitution. One of the primary degradation products is aprepitant. As aprepitant is generated, it will precipitate from an aqueous solution. This poses a challenge in preparing ready-to-use or ready-to-dilute compositions of Fosaprepitant dimeglumine.
It is an object of the invention to provide a stable ready-to-use liquid compositions of fosaprepitant suitable for parenteral administration. It is an object of the invention to provide a stable ready-to-dilute liquid compositions of fosaprepitant for parenteral administration. It is an object of the invention to provide liquid compositions of fosaprepitant which do not degrade to aprepitant. It is an object of the invention to provide a stable composition of fosaprepitant containing less than 10% w/v of aprepitant, even when stored over prolonged periods of time.
The details of one or more embodiments are set forth in the descriptions below. Other features, objects, and advantages will be apparent from the description and from the claims.